Direct Induction of Trophoblast Stem Cells from Murine Fibroblasts

Trophoblast stem cells (TSCs) arise from the first cell fate decision in the developing embryo and generate extra-embryonic lineages, giving rise to the fetal portion of the placenta. Mouse embryonic and extra-embryonic lineages are strictly separated by a distinct epigenetic barrier, which is not f...

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Bibliographic Details
Published in:Cell stem cell 2015-11, Vol.17 (5), p.557-568
Main Authors: Kubaczka, Caroline, Senner, Claire E., Cierlitza, Monika, Araúzo-Bravo, Marcos J., Kuckenberg, Peter, Peitz, Michael, Hemberger, Myriam, Schorle, Hubert
Format: Article
Language:English
Subjects:
Animals
Cell Cycle
Cell Lineage
Cell Transdifferentiation
Cells, Cultured
Embryonic Stem Cells - cytology
Fibroblasts - cytology
Mice
Trophoblasts - cytology
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Summary:Trophoblast stem cells (TSCs) arise from the first cell fate decision in the developing embryo and generate extra-embryonic lineages, giving rise to the fetal portion of the placenta. Mouse embryonic and extra-embryonic lineages are strictly separated by a distinct epigenetic barrier, which is not fully overcome following expression of TSC-determining factors in embryonic stem cells. Here, we show that transient expression of Tfap2c, Gata3, Eomes, and Ets2 is sufficient to reprogram mouse embryonic fibroblasts and post-natal tail-tip-derived fibroblasts into induced TSCs (iTSCs) and surmount the epigenetic barrier separating somatic from extra-embryonic lineages. iTSCs share nearly identical morphological characteristics, gene expression profiles, and DNA methylation patterns with blastocyst-derived TSCs. Furthermore, iTSCs display transgene-independent self-renewal, differentiate along extra-embryonic lineages, and chimerize host placentas following blastocyst injection. These findings provide insights into the transcription factor networks governing TSC identity and opportunities for studying the epigenetic barriers underlying embryonic and extra-embryonic lineage segregation. [Display omitted] •Direct induction of TSC fate from mouse fibroblasts by four transcription factors•Induced TSCs are stable, transgene independent, and functional in vivo•The transcriptomes and methylomes of iTSCs and bona fide TSCs are highly similar Kubaczka et al. report that transient expression of Tfap2c, Gata3, Eomes, and Ets2 can reprogram murine fibroblasts into induced trophoblast stem cells (iTSCs). iTSCs are fully functional and exhibit full demethylation of key loci, showing that the lineage barrier between somatic and extra-embryonic cell fates can be overcome.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2015.08.005